THE EFFECT OF PREINCUBATION WITH CIMETIDINE ON THE N-HYDROXYLATION OF DAPSONE BY HUMAN LIVER-MICROSOMES

被引:22
作者
TINGLE, MD
COLEMAN, MD
PARK, BK
机构
[1] Department of Pharmacology and Therapeutics, Liverpool
基金
英国惠康基金;
关键词
DAPSONE; METABOLISM; CIMETIDINE; INHIBITION; METHEMOGLOBINEMIA;
D O I
10.1111/j.1365-2125.1991.tb05623.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon(R) chambers are separated by a semi-permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/- NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0-1000-mu-M) and NADPH prior to the addition of dapsone (100-mu-M) and NADPH (1 mM) resulted in a concentration-dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/- 47 to 40 +/- 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration-dependent reduction in methaemoglobin measured (from 7.1 +/- 0.7 to 3.5 +/- 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone-dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.
引用
收藏
页码:120 / 123
页数:4
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